A number of publications are cited herein in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Each of these publications is incorporated herein by reference in its entirety into the present disclosure, to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.
Throughout this specification, including the claims which follow, unless the context requires otherwise, the word “comprise,” and variations such as “comprises” and “comprising,” will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a pharmaceutical carrier” includes mixtures of two or more such carriers, and the like.
Ranges are often expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent “about,” it will be understood that the particular value forms another embodiment.
This disclosure includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
Herpesviridae
The herpesviridae are a large family of DNA viruses, also known as herpesviruses. There are a number of distinct viruses in this family that are known to cause disease in humans, including: herpes simplex virus 1(HSV-1); herpes simplex virus 2 (HSV-2); varicella zoster virus (VZV); Epstein-Barr virus (EVB); cytomegalovirus (CMV); roseolovirus; and Kaposi's sarcoma-associated herpesvirus (KSHV).
Both the herpes simplex viruses (HSV-1 and HSV-2) and the varicella zoster virus (VZV) belong to the same viral subfamily (alphaherpesvirinae).
Herpes Simplex Virus (HSV)
Herpes simplex viruses have a diameter of 140 to 180 nm, and therefore are classed among the large viruses. They possess an ikosaedric capsid which contains a linear, double stranded DNA. The capsid is surrounded by a virus envelope; this fact causes the sensitiveness of the virus to soaps, detergents and mild disinfectants.
About 80% of the worldwide population is positive for HSV antibodies (see, e.g., Whitley, 1990) and consequently the herpes simplex virus is distributed all over the world. In the United States, the lifetime prevalence of recurrent herpes labialis is estimated at 20% to 40%, with approximately 100 million episodes occurring in the country every year (see, e.g., Young et al., 1988). In Switzerland, about 70% of the adult population is positive for HSV-1 antibodies and about 20% is positive for HSV-2 antibodies (see, e.g., Buenzli et al., 2004).
HSV-1 is transmitted via saliva contact, or smear infection, whereas HSV-2 is transmitted via close mucosa contact. HSV-1 is normally acquired during infancy, via the oral mucosa where it causes gingivostomatitis (a very painful inflammation in the mouth). Afterwards the viruses migrate along the axons to the CNS (central nervous system), where they stay latent in the ganglion trigeminale (Gasseri). After reactivation (endogenous recrudescence), which can be caused by psychic stress, isolation, fever, traumas, menstruation, other infections or immunosuppressive therapy, they migrate to the periphery in the same way, where they cause cold sores (Herpes labialis). There is a very high density of nerve endings in the lips; those epithelial layers are important for the reproduction of the virus.
Despite a present immunity, these recrudescences are always possible, because the virus migrates along the nerve pathway and does not migrate into the intercellular space. This means that the immune system has no possibility to attack the viruses. Some complications are therefore possible; one of them is herpetic keratoconjunctivitis or the highly lethal Herpes encephalitis (which has an untreated lethality of up to 80%).
Initial infection with HSV-2 normally takes place during sexual intercourse and concerns the urogenital tract. This infection can happen even though the host tests positive for HSV-1. The HSV-2 virus stays latent in the lumbosacral ganglions or in the peripheral tissue from where it causes the so called Herpes genitalis symptoms. Neurological complications are rare and more benign than with HSV-1 infection. However, there is one complication with high mortality: the infection of the neonate (Herpes neonatorum).
Herpes Labialis
Herpes labialis is a disease which is triggered by the herpes simplex virus (HSV). There are two types of Herpes simplex viruses which are called HSV-1 and HSV-2, both of which belong to the genus of the Simplex viruses of the family Herpes viridae.
The incubation time of Herpes labialis is typically from 2 to 12 days. The initial signs and symptoms of reactivation of Herpes labialis include: a feeling of tension; hypersensitivity of the skin; tingling, burning, and/or itching followed by a delayed reepithelialisation; crusting (which is often pus-filled) and erosions. In some rare cases, the lymph nodes can be swollen.
In addition to the neurologic and internistic diagnostic procedure, there is also a possibility to detect the virus in the blood, with antibody testing. However, confirmation of the specific virus is only performed in severe cases. Even in generalized and disseminated HSV-infections, the detection of HSV-IgG and HSV-IgM antibodies can not be done or can only be done very late.
The lytic cycle of HSV in epithelial cells includes entry, uncoating, viral transcription, DNA replication in the nucleus, particle assembly and exit from the cell. As a result of this process, a primary infection is triggered. Some of the viruses enter sensory neuron terminals and travel retrogradely to the nucleus, where they establish latency. Epithelial cells are re-infected following anterograde transport of viral particles shedding from the neuron. This re-infection leads to asymptomatic shedding or recurrent lesions.
Current Treatments for Herpes Labialis
For the abatement of Herpes labialis, a number of antivirals are available. The “gold standard”, however, is acyclovir, a nucleoside analog of the guanine base. Because of its low bioavailability, some other antivirals have been developed (e.g., pencyclovir and its derivatives famciclovir and valaciclovir etc.). The acyclovir molecule is transformed (only in infected cells) to acyclovir-monophosphate by the viral thymidine kinase. This kinase is much more effective on phosphorylation, than the cellular thymidine kinase. Afterwards, the monophosphate form of acyclovir is converted into the triphosphate form (acyclovir-triphoshate) by cellular thymidine kinase.
For slight or rare outbreaks of Herpes labialis, the application of 5% acyclovir cream is sufficient. This cream is applied directly onto the cold sore 5 times daily, typically for 5 days, and a treatment period of 10 days should not be exceeded.
The current treatment for episodic recurrent Herpes labialis is as follows:
TABLE 1Acyclovir (Zovirax ®)5 × 200 mg p.o. per day for 5 daysValaciclovir (Valterx ®)2 × 500 mg p.o. per day for 5 daysFamciclovir (Famvir ®)2 × 125 mg p.o. per day for 5 days
The current treatment for virostatic suppression therapy for frequent relapses of recurrent
Herpes labialis is as follows:
TABLE 2Acyclovir2 × 400 mg p.o. per day for at least 6-12 months(Zovirax ®)Valaciclovir1 × 500 mg p.o. per day for at least 6-12 months; or(Valterx ®)2 × 500 mg p.o per day for at least 6-12 monthsFamciclovir2 × 250 mg p.o. per day for at least 6-12 months(Famvir ®)
The above treatments are very expensive, especially when long-term treatment is required. This often also causes a reduction in patient compliance with the treatment regimen. Additionally, in recent years, there is an increase in the amount of viruses resistant to acyclovir, which can also reduce treatment efficacy.
Consequently, there is an important need for alternative treatments for HSV infections and for diseases and disorders associated with, triggered by, or caused by, infection by herpes simplex virus (HSV), including, for example, herpes labialis.
The inventors have discovered that, surprisingly and unexpectedly, polyethylene glycol (PEG) applied topically onto the lips and surrounding facial skin of a patient reduces the rate of relapse, delays relapse, and/or prevents relapse of herpes labialis.
Many treatments for herpes labialis have been described. Usually, the treatment involves the use of a formulation comprising one or more therapeutic agents (e.g., one or more agents for the treatment of herpes labialis and/or the underlying viral infection). In some cases, the formulation additionally includes polyethylene glycol (PEG).
However, in each case, the PEG is included for its formulation properties, and not because of any recognition of its therapeutic value. Nowhere has it been suggested that polyethylene glycol itself is useful or effective in therapy for viral infections, let alone for reducing the rate of relapse, delaying relapse, and/or preventing relapse of herpes labialis, herpes genitalis, or herpes zoster.
Also, in each case, the formulation is intended for treatment of acute herpes labialis (e.g., treatment of the symptoms of herpes labialis; to reduce the severity of the symptoms; to reduce the duration of the relapse; to promote healing, etc.). In each case, the formulation is administered at the beginning of relapse (i.e., in the prodromal phase) or during the relapse (i.e., in the acute phase). Nowhere has it been suggested that such formulations should be adminstered as a prophylactic, even when no symptoms appear, in order to reduce the rate of relapse, delay relapse, and/or prevent relapse.
For example, international patent publication number WO 2008/087034 A2 describes cyclodextrin formulations and their use in the treatment of viral infections, including treatment of cold sores. See, e.g., page 3, lines 23-24 therein. The formulations may contain, for example, polyethylene glycol, as an optional additional component. See, e.g., pages 15-16 therein. Nowhere in this document is there any teaching or suggestion that polyethylene glycol itself is useful or effective in therapy for viral infections, such as herpes labialis. Nowhere in this document is there any teaching or suggestion that polyethylene glycol itself is useful or effective for reducing the rate of relapse, delaying relapse, and/or preventing relapse of herpes labialis, herpes genitalis, or herpes zoster.
Similarly, U.S. Pat. No. 4,762,715 describes lipstick formulations comprising certain antiherpetic agents (heparin and zinc sulphate) for treatment of herpes labialis. Example 1 therein describes the preparation of a lipstick using a mixture of: PEG 1000; PEG 4000; PEG 400; polyoxyethylene sorbitan monostearate; polyoxyethylene sorbitan monooleate; heparin sodium; and zinc sulphate heptahydrate. Nowhere in this document is there any teaching or suggestion that polyethylene glycol itself is useful or effective in therapy for viral infections such as herpes labialis. Nowhere in this document is there any teaching or suggestion that polyethylene glycol itself is useful or effective for reducing the rate of relapse, delaying relapse, and/or preventing relapse of herpes labialis, herpes genitalis, or herpes zoster. Instead, polyethylene glycol was chosen as a preferred carrier, as is often the case in pharmaceutical formulation.